Methods for treating intrapulmonary infections

Abstract

This disclosure relates to the treatment of intrapulmonary bacterial infections, including treatment of nosocomial pneumonia lung infections with pharmaceutical compositions containing the cephalosporin ceftolozane.

1 . A method of treating an infection in a patient in need thereof, the method comprising intravenously administering to the patient a pharmaceutical composition in a dose of about 1 gram of ceftolozane active and 0.5 gram of tazobactam active repeatedly administered every 8 hours, with each dose administration providing a mean plasma Area Under Curve (AUC,0-t) of about 158.5 micrograms hour/ml of ceftolozane and a mean plasma Area Under Curve (AUC,0-t) of about 19.3 micrograms hour/ml of tazobactam to treat the infection in said patient, wherein AUC,0-t is the area under the concentration time curve from the time of the dose to the end of the dosing interval. 
     
     
         2 . The method of  claim 1 , wherein the ceftolozane is administered in an amount effective to provide a concentration of at least 8 micrograms/mL in the blood of the patient for at least 60% of the interval between doses. 
     
     
         3 . The method of  claim 1 , wherein the pharmaceutical composition is repeatedly administered as a combined ceftolozane/tazobactam preparation. 
     
     
         4 . The method of  claim 1 , wherein the ceftolozane and the tazobactam are each separately administered to the patient. 
     
     
         5 . The method of  claim 1 , wherein the pharmaceutical composition is repeatedly administered as a 60-minute infusion every 8 hours. 
     
     
         6 . The method of  claim 5 , wherein the pharmaceutical composition is repeatedly administered as a combined ceftolozane/tazobactam preparation. 
     
     
         7 . The method of  claim 6 , wherein the ELF penetration ratio of the pharmaceutical composition is about 0.48 for ceftolozane and about 0.44 for tazobactam. 
     
     
         8 . The method of  claim 1 , wherein the ceftolozane and tazobactam are administered for a 10 day course of treatment. 
     
     
         9 . The method of  claim 1 , wherein the infection comprises  Pseudomonas aeruginosa.   
     
     
         10 . The method of  claim 1 , wherein the ceftolozane is a ceftolozane hydrogen sulfate salt. 
     
     
         11 . The method of  claim 1 , wherein the ceftolozane is (6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method of  claim 1 , wherein the infection is a complicated intra-abdominal infection. 
     
     
         13 . The method of  claim 1 , wherein the infection is a complicated urinary tract infection. 
     
     
         14 . The method of  claim 1 , wherein the tazobactam and the ceftolozane are the only antibiotics administered to treat said infection. 
     
     
         15 . A method of treating an infection in a patient in need thereof, the method comprising intravenously administering to the patient a pharmaceutical composition in a single dose of about 1 gram of ceftolozane active and 0.5 gram of tazobactam active repeatedly administered every 8 hours, wherein the pharmaceutical composition is administered in an amount effective to provide a ceftolozane concentration of at least 8 micrograms/mL in the blood of the patient for at least 60% of the interval between doses. 
     
     
         16 . The method of  claim 15 , wherein the pharmaceutical composition is administered to the patient every 8 hours as a 60-minute infusion to produce in said patient an epithelial lining fluid (ELF) Area Under Curve (AUC,0-t) of about 75.1 micrograms hour/ml of ceftolozane and a mean ELF Area Under Curve (AUC,0-t) of about 8.5 micrograms hour/ml of tazobactam to treat the infection in said patient, wherein AUC,0-t is the area under the concentration time curve from the time of the dose to the end of the dosing interval. 
     
     
         17 . The method of  claim 15 , wherein the ceftolozane is a ceftolozane hydrogen sulfate salt. 
     
     
         18 . The method of  claim 15 , wherein the ceftolozane is ((6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 15 , wherein the pharmaceutical composition dose is repeatedly administered as a combined ceftolozane/tazobactam preparation. 
     
     
         20 . The method of  claim 15 , wherein the pharmaceutical composition is repeatedly administered as a 60-minute infusion every 8 hours. 
     
     
         21 . The method of  claim 15 , wherein the infection is a complicated intra-abdominal infection. 
     
     
         22 . The method of  claim 15 , wherein the infection is a complicated urinary tract infection. 
     
     
         23 . A method of treating an infection in a subject comprising the step of intravenously administering ceftolozane and tazobactam in about a 2:1 weight ratio every 8 hours as a 1 hour infusion to a subject in need thereof. 
     
     
         24 . The method of  claim 23 , comprising administering to a subject a dose with a total of 0.5 grams of tazobactam active and a total of 1 gram of ceftolozane active. 
     
     
         25 . The method of  claim 23 , comprising administering a total of 3 g of ceftolozane per day and 1.5 g of tazobactam per day to the subject, and the tazobactam and the ceftolozane are the only antibiotics administered to treat said infection. 
     
     
         26 . A solution comprising 0.5 grams of tazobactam active and 1 gram of ceftolozane active, wherein parenteral administration of said solution to a selected human treatment group every 8-hours as a 60-minute infusion produces in said selected human treatment group a mean plasma Area Under Curve (AUC,0-t) of about 158.5 micrograms hour/ml of ceftolozane and a mean plasma Area Under Curve (AUC,0-t) of about 19.3 micrograms hour/ml of tazobactam to treat the infection in said human treatment group, wherein AUC,0-t is the area under the concentration time curve from the time of the dose to the end of the dosing interval. 
     
     
         27 . The solution of  claim 26 , wherein said solution administered to the human treatment group every 8 hours as a 60-minute infusion produces in said selected human treatment group a mean epithelial lining fluid (ELF) Area Under Curve (AUC,0-t) of about 75.1 micrograms hour/ml of ceftolozane and a mean ELF Area Under Curve (AUC,0-t) of about 8.5 micrograms hour/ml of tazobactam to treat the infection in said human treatment group, wherein AUC,0-t is the area under the concentration time curve from the time of the dose to the end of the dosing interval. 
     
     
         28 . The solution of  claim 26 , wherein the ceftolozane is a ceftolozane hydrogen sulfate salt. 
     
     
         29 . The solution of  claim 26 , wherein the ceftolozane is ((6R,7R)-3-[5-Amino-4-[3-(2-aminoethyl)ureido]-1-methyl-1H-pyrazol-2-ium-2-ylmethyl]-7-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(Z)-1-carboxy-1-methylethoxyimino]acetamido]-3-cephem-4-carboxylic acid, or a pharmaceutically acceptable salt thereof. 
     
     
         30 . The solution of  claim 26 , wherein the selected human treatment group has a treatment-emergent adverse events in Table 4 during treatment with the solution: 
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Subjects with at least 1 TEAE 
                   5 (20.0) 
                   6 (23.1) 
                 
                     
                   Diarrhea 
                   1 (4.0) 
                   3 (11.5) 
                 
                     
                   Viral Upper Respiratory Infection 
                   1 (4.0) 
                   0 (0) 
                 
                     
                   Musculoskeletal Chest Pain 
                   1 (4.0) 
                   0 (0) 
                 
                     
                   Somnolence 
                   1 (4.0) 
                   0 (0) 
                 
                     
                   Hematuria 
                   1 (4.0) 
                   0 (0) 
                 
                     
                   Cough 
                   1 (4.0) 
                   0 (0) 
                 
                     
                   Type I Hypersensitivity 
                   0 (0) 
                   1 (3.8) 
                 
                     
                   Alanine Aminotransferase Increased 
                   0 (0) 
                   1 (3.8) 
                 
                     
                   Aspartate Aminotransferase Increased 
                   0 (0) 
                   1 (3.8) 
                 
                     
                   Blood Creatine Phosphokinase Increased 
                   0 (0) 
                   1 (3.8) 
                 
                     
                   Hyperkalemia 
                   0 (0) 
                   1 (3.8)